Phosphorylation of cardiac voltage‐gated sodium channel: Potential players with multiple dimensions

Abstract

Cardiomyocytes are highly coordinated cells with multiple proteins organized in micro domains. Minor changes or interference in subcellular proteins can cause major disturbances in physiology. The cardiac sodium channel (NaV1.5) is an important determinant of correct electrical activity in cardiomyocytes which are localized at intercalated discs, T‐tubules and lateral membranes in the form of a macromolecular complex with multiple interacting protein partners. The channel is tightly regulated by post‐translational modifications for smooth conduction and propagation of action potentials. Among regulatory mechanisms, phosphorylation is an enzymatic and reversible process which modulates NaV1.5 channel function by attaching phosphate groups to serine, threonine or tyrosine residues. Phosphorylation of NaV1.5 is implicated in both normal physiological and pathological processes and is carried out by multiple kinases. In this review, we discuss and summarize recent literature about the (a) structure of NaV1.5 channel, (b) formation and subcellular localization of NaV1.5 channel macromolecular complex, (c) post‐translational phosphorylation and regulation of NaV1.5 channel, and (d) how these phosphorylation events of NaV1.5 channel alter the biophysical properties and affect the channel during disease status. We expect, by reviewing these aspects will greatly improve our understanding of NaV1.5 channel biology, physiology and pathology, which will also provide an insight into the mechanism of arrythmogenesis at molecular level.

Improved sequence-based prediction of interaction sites in α-helical transmembrane proteins by deep learning

“…The human cardiac voltage-gated sodium channel Nav1.5, encoded by the gene SCN5A, is expressed in the cardiomyocyte sarcolemma to carry an inward depolarizing current during phase 0 of the cardiac action potential [92] . According to the BioGRID database Nav1.5 has 22 interaction partners, and we identified additional 21 interaction partners based on literature analysis ( Supplementary Table S27 ) [93] , [94] , [95] , [96] , [97] , [98] , [99] . Only a small number of interaction sites have been described in these studies, of which most are situated in the C -terminal portion of Nav1.5 (positions 1773–2016, indicated by blue triangles in Fig.…”

Protein kinases mediate anti-inflammatory effects of cannabidiol and estradiol against high glucose in cardiac sodium channels

“…7). PK-A phosphorlylates S525 and S528, while PK-C phosphorylates S1503 in human Nav1.5 (Iqbal & Lemmens-Gruber, 2019). There are conflicting reports regarding the effects of PK-A and PK-C activation on the voltage-dependence and kinetics of Nav1.5 gating.…”

“…There are conflicting reports regarding the effects of PK-A and PK-C activation on the voltage-dependence and kinetics of Nav1.5 gating. These differences could be attributed to different voltage protocols, different holding potentials, different concentrations or type of PK-activators, or different cell lines used in the various studies (Aromolaran, Chahine & Boutjdir, 2018; Iqbal & Lemmens-Gruber, 2019). Despite this discrepancy, both PK-A or PK-C destabilize Nav fast inactivation and hence increase INap, which is strongly correlated to prolonged APD as shown in our findings (Fig.…”

GeneLab Database Analyses Suggest Long-Term Impact of Space Radiation on the Cardiovascular System by the Activation of FYN Through Reactive Oxygen Species

“…Using these datasets, we hypothesized that there are common long-term molecules and pathways modulating the cardiovascular system due to radiation effects during spaceflight. Using a systems biology approach, we were able to suggest a novel mechanism through the FYN pathway [32,33,34,35] that the cardiovascular system uses to reduce reactive oxygen species (ROS) levels when exposed to space radiation. Briefly, FYN is a member of the Src family of tyrosine kinases that has been previously shown to be heavily involved with the cardiovascular system through cardiomyocyte remodeling [36,37] and also leads to activation due to ROS [32,33,38,39].…”

“…Using a systems biology approach, we were able to suggest a novel mechanism through the FYN pathway [32,33,34,35] that the cardiovascular system uses to reduce reactive oxygen species (ROS) levels when exposed to space radiation. Briefly, FYN is a member of the Src family of tyrosine kinases that has been previously shown to be heavily involved with the cardiovascular system through cardiomyocyte remodeling [36,37] and also leads to activation due to ROS [32,33,38,39]. In addition to FYN’s involvement with the cardiovascular system, it has also been reported to be a tumor suppressor [40,41], a key player in controlling immune receptor signaling status and inflammation [42], and has been shown to affect myelination of the central nervous system through crosstalk with Erk1/2 signaling [43].…”